The major histocompatibility complex (MHC) plays key roles in controlling both adaptive and innate immune systems. In the adaptive immune system, both MHC class I and class II antigens recognize, bind and present peptides to cytotoxic and helper T-cells, respectively, and initiate cell-to-cell communication between antigen presenting cells and T-cells by forming immunological synapses and activate both subtypes of T-cells for both celluar and humoral immune systems. In addition, a number of gene clusters in this complex encode proteins which play important roles for antigen processing (proteosome subunit, LMP2 & 7, antigen transporter, TAP1 & 2, antigen loading for class I antigen, Tapasin, antigen loading for class II antigens, DM & DO molecules). In the innate immune system, both classical (HLA-A,-B,-C in human) and non-classical class I (HLA-E) antigens, plus class I-related molecules (MIC-A, -B) interact with NK receptors (KIR & NKG antigens in human and Ly-49 and NKG antigens in mouse) and inhibit and activate NK-cell functions. In addition to the immunological importance, the MHC provides important tools to study molecular evolution. Extremely polymorphic features of both class I and class II antigens identified in most vertebrates provide numerous numbers of peptide binding grooves for MHC class I and II antigens in order to adapt various pathogens. Natural and balancing selections play pivotal roles to generate and maintain these polymorphisms. The nature of multigene clusters of the MHC genes also provides a number of theories to explain the genesis of the MHC. Also, paralogous chromosomal regions found in three other locations in human (chr. 6p21.3 for MHC, 9q33-34, 1, 19 for the others) and jawed vertebrates stimulate discussions for the origin of the MHC. A large-scale sequencing project for the HLA has been launched and completed for the 3.6 Mb of the classical class I, II, & III regions to reveal the molecular history of this important gene complex, and has identified 224 tightly linked genes, including 128 expressed genes, and 96 pseudogenes. More recently, the MHC expands to 4.6 Mb, including five subregions, 1) extended class II (280 kb); 2) class II (700 kb); 3) class III (1000 kb); 4) class I (1600 kb); 5) extended class I (1000 kb). In contrast of this large complex structure in HLA, the chicken MHC B-locus presents a "minimal essential MHC" disposition extending 92 kb and including 19 functional genes, raising questions about structures of other MHC systems. The feline MHC has been studied for an approach to comparative gene organization of this multigene cluster in mammals. A composite 758,291-bp sequence was determined from five PAC and four BAC clones which spanned the classical and extended class II regions of the domestic cat MHC. Forty-four coding genes were identified by GENESCAN and BLASTP algorithms between HSET (centromeric extreme of extended class II) and BTLII (telomeric of classical class II region). Comparison of the gene organization of the MHC class II region between the mouse, domestic cat, and human indicated size differences of around 250 kb between these three species showing 495 kb, 758 kb, and 998 kb, in the mouse, domestic cat, and human, respectively. These size differences appear to reflect both the presence/absence of genes plus moderate differences in gene density in each MHC. The observed gene densities were one gene every 13.7 kb, 17.2 kb and 18.1 kb in the mouse, domestic cat, and human MHC class II region, respectively. The feline MHC class II region lacked functional DP genes, also lacked the entire DQ region, but maintained three alpha and four beta genes in its DR region, which appear to be generated by three gene duplications and two inversions. Three pseudogenes, vacuolar ATPase, glyceraldehyde 3'-phosphate dehydrogenese (GAPDH) and SURF-3 (L7a ribosomal protein) genes were translocated in the cat MHC class II region. Comparative analysis of interspersed repeat sequences in the MHC class II regions among human, domestic cat, and mouse indicated that although five types of interspersed repeats: SINEs, LINEs, LTR transposons, STRs (short tandem repeats) and DNA transposons, were common to all three species, there were distinct differences in the proportion of the repeat sequences in each MHC class II region. The numerity of the microsatellite motif was highest in the cat (811 loci), lower in human (344 loci) and intermediate in the mouse (524 loci). The frequency of dinucleotide repeats in the human class II sequence was approximately four to six times lower than in domestic cat and mouse.